Chronic inflammation is a hallmark of late stage rheumatoid arthritis (RA), driven by a multitude of factors including cytokines and chemokines, ultimately resulting in joint destruction. Targeting of individual cytokines in this process has shown efficacy in RA, however, these treatments are not effective for all patients suggesting that new therapies are required. Manzamines are a unique class of natural marine products with significant biological activity isolated from sponges collected from the ocean floor. Over 50% of novel compounds patented from all marine organisms describe sponge-derived molecules from this same chemical class, demonstrating tremendous potential for this group of molecules. Recent cell culture studies strongly suggest that one manzamine in particular, manzamine A (MZA), has potent anti-inflammatory properties on activated human macrophages, in the absence of toxicity. Studies using MZA to treat malaria in rats demonstrate exciting changes that are consistent with desired effects for RA patients. For example, two mediators which promote inflammation were significantly lowered, including tumor necrosis factor (TNF)-1 and interferon-3. TNF-1 is often over-produced in the RA joint late in disease, contributing to inflammation. On the other hand, levels of a protein which can naturally act to reduce inflammation in the joint, known as interleukin-10, were increased by MZA. Our preliminary data suggests that these three beneficial changes are only the "tip of the iceberg", and that MZA holds many additional, yet unrecognized, anti-inflammatory properties specifically relevant to RA. While literally thousands of marine products are being explored for the treatment of cancer, there are very limited comparable studies for the treatment of arthritis. No studies testing the anti-inflammatory potential of any manzamine have been conducted in RA. Oral and intravenous studies in rats given MZA suggest it is an excellent compound for pharmaceutical development. It has a very long half-life, good stability, fine absorption, adequate oral bioavailability, and low toxicity. The outlook for large-scale production of MZA is also very good, with many groups working to synthesize it from scratch or to isolate it from new sources. We developed a unique collaboration with an oceanographic institute and obtained more than enough purified compound to study the effects of MZA in arthritis. Here, we propose to examine the potential application of MZA to RA with regards to its: 1) toxicity;2) ability to alter inflammatory mediators in a manner that benefits RA patients;3) ability to reduce the influx of immune system cells to the joint;and 4) mechanism. Based on our preliminary data and the background we review, we are very optimistic about the future potential of MZA as a novel treatment for RA. PUBLIC HEALTH RELEVANCE. While many new therapies have become available in the rheumatologists'arsenal in the last decade to treat rheumatoid arthritis (RA), significant RA-associated morbidity still exists. Therefore, the search for additional and improved anti-inflammatory agents with low side effects is warranted. This application has high relevance to RA in that it will specifically focus on the anti-inflammatory potential of a unique compound, manzamine A, on RA synovial tissue and other relevant cell types.